Background:Currently, the survival of men who have failed docetaxel-based chemotherapy for metastatic CRPC is poor, on the order of 12-14 months, and for men with an elevated CTC count, this figure is even further reduced. Two of the principal molecular mechanisms of progression to the castrate-resistant state include loss of the PTEN tumor suppressor pathway and alterations in androgen receptor signaling through mutation or amplification. These pathways contribute to increased PI3K/mTOR signaling and AR-dependent signaling, respectively, which leads to progressive tumor growth, survival, treatment resistance, and metastasis. Based on this rationale, we are conducting a single arm phase II study of the mTOR inhibitor temsirolimus (Torisel) in combination with anti-androgen therapy, in order to assess the clinical activity of this combination on disease progression and changes in PSA and CTC counts. This trial is funded by the NCCN. Methods:Eligible men will have metastatic progressive CRPC based on RECIST, bone scan, or PSA criteria and are required to have a CTC count ≥10 cells per 7.5 mL whole blood as measured by standard Cellsearch methods. Prior chemotherapy is allowed. Men must have resolution of prior grade 2 toxicities and be at least 2 weeks from completion of palliative radiation, 4 weeks from prior systemic therapies, have adequate organ function (WBC≥3K, ANC≥1.5K, platelets≥75L, Hgb≥9 g/dl, Cr ≤2.0xULN, AST/ALT ≤2.5xULN, normal bilirubin), and have a KPS≥60. Patients with serious underlying cardiovascular, autoimmune, pulmonary, or other medical comorbidities are excluded. Patients will initially receive temsirolimus 25 mg IV weekly at Duke University, and upon PSA/CTC progression, an anti-androgen will be added. The combination will be continued until progression defined by PCWG2 criteria. PSA, LDH, imaging, CTC count, and changes in CTC biology including measures of epithelial plasticity and genomic signatures will be measured every 8 weeks. The primary endpoint is the proportion of men with a favorable CTC count conversion to <5 cells/7.5 mL over time. 1/20 patients have been accrued as of December 2009.